Proton pump (H+/K+-ATPase) inhibitors powerfully inhibit secretion of gastric acid, which is the major cause of peptic ulcers. Therefore, the inhibitors are widely used as remedies for peptic ulcers. Examples of proton pump inhibitors heretofore known (hereinafter referred to as “existing proton pump inhibitors”) include omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole (Japanese Patent Application Laid-Open (kokai) No. 54-141783, WO94/27988, Japanese Patent Application Laid-Open (kokai) No. 61-50978, Japanese Patent Application Laid-Open (kokai) No. 64-6270, and Japanese Patent Application Laid-Open. (kokai) No. 61-22079).
In recent years, analyses of pharmacokinetics have revealed that existing proton pump inhibitors are primarily metabolized by CYP2C19, which is an isoform of cytochrome P450 (CYP) (Clin. Pharmacokinet., 1996, Vol. 31, p 9-28; U.S. Pat. No. 5,877,192; Aliment. Pharmacol. Ther., 2001, Vol. 15, p 793-803). Also, many of the existing proton pump inhibitors have been known to induce CYP1A2, another isoform of cytochrome P450 (Xenobiotica, 1997, Vol. 27, No. 1, p 1-9).
Genetic polymorphism of CYP2C19 has been identified in humans, and accordingly, some humans are poor metabolizers which were hereditarily deficient in CYP2C19 activity, whereas others are extensive metabolizers exhibiting CYP2C19 activity. Thus, it has been accepted that, when existing proton pump inhibitors—which are metabolized by CYP2C19—are administered to extensive metabolizers in usual doses, in some cases, the efficacy of the inhibitors they produce in response is inferior to that produced by poor metabolizers (Ann. Intern. Med., 1998, Vol. 129, 1027-1030; Gastroenterology, 2001, Vol. 120, Suppl. 1., A-432, (#2203); and Gastroenterology, 2001, Vol. 120, Suppl. 1., A-435, (#2219)). Therefore, one approach toward causing extensive metabolizers to respond to these drugs as effectively as do poor metabolizers is to administer the drugs at higher doses to extensive metabolizers. However, administration at such a high dose is not necessary for poor metabolizers, and raises the incidence of side effects.
For the above-described reasons, when an existing proton pump inhibitor is to be administered to a subject, a beneficial course of action is to first identify the CYP2C19 genotype of that subject, and then using the genotype information as the basis for determining an effective dose of the inhibitor which is appropriate for that subject (Aliment. Pharmacol. Ther., 1999, Vol. 13, p453-458).
As mentioned hereinabove, some existing proton pump inhibitors induce enzymes of the CYP1A family. When enzyme induction occurs, pharmacological activities of theophylline, caffeine, and similar drugs which are metabolized by these enzymes are lost at an early stage, inviting the risk of drug interaction in which the intended therapeutic effect cannot be obtained (Eur. J. Clin. Pharmacol., 1995, Vol. 48, p391-395).
It is also known that some procarcinogens are activated when they are ingested and metabolized by CYP1A subfamily members, and thereby exhibit carcinogenicity. Thus, conceivably, when administration of a proton pump inhibitor that can induce a member isoform of the CYP1A family in fact results in induction of the isoform, activation of the procarcinogens is promoted, raising the risk of increased cancer incidence (Gastroenterology, 1990, Vol. 99, p737-747).
Because of these factors, there has been a demand for proton pump inhibitors which, without being affected by enzyme activity of CYP2C19, will ensure that patients who receive the inhibitors can equally enjoy proper therapeutic effects at the same dose and which, due to the absence of induction of members of the CYP1A family, have low risk of inducing drug interaction attributed to the increase in the enzymatic activities of such members, as well as low risk of developing cancer.